Glutathione

THE ROLE OF GLUTATHIONE

Glutathione, a tripeptide consisting of γ-l-glutamyl-l-cysteinyl-glycine, is the most important low molecular weight antioxidant synthesized in cells^[1]. It plays a pivotal role in reducing oxidative stress, maintaining redox balance, enhancing metabolic detoxification, and regulating the immune system. Suboptimal or insufficient glutathione levels have been associated to a variety of chronic, age-related illnesses, including neurodegeneration, mitochondrial malfunction, and even cancer^[2]. Glutathione is synthesized by the sequential addition of cysteine to glutamate followed by the addition of glycine. The sulfhydryl group(-SH) of the cysteine is involved in reduction and conjugation reactions which are the most significant functions of glutathione. These reactions allow peroxides and several xenobiotic substances to be removed; nevertheless, glutathione is also involved in cell cycle regulation^[1].

NATURAL DIETARY SOURCES OF GLUTATHIONE

Natural sources of glutathione include fresh fruits, vegetables, and nuts. Tomatoes, avocados, oranges, walnuts, and asparagus are just a few of the popular foods that help to increase levels of glutathione in the body. Whey protein is another high-glutathione food that has been used to enhance systemic glutathione levels in cystic fibrosis^[3]. The body reproduces its own glutathione and it can be depleted by diet, pollution, toxins, medications, stress, trauma, aging, infections and radiation; and glutathione is normally recycled in the body^[4].

BIOLOGICAL ACTIVITY

Glutathione exists in two interconvertible forms, reduced glutathione (GSH) and oxidized glutathione (GSSG). GSH is the predominant intracellular form, which acts as a strong antioxidant and defends against toxic compounds and xenobiotics. GSH is constantly oxidized to GSSG by the enzyme glutathione peroxidase during this process. To maintain the intracellular redox balance, GSH is replenished through the reduction of GSSG by glutathione reductase enzyme^[3].

GLUTATHIONE AND HUMAN PIGMENTATION

Melanin in human skin is a polymer of various indole compounds synthesized from L-tyrosine with tyrosinase being the rate limiting enzyme. The skin color is determined by the ratio of two different types of melanin found in the skin, black-brown colored eumelanin and yellow-red pheomelanin. Lighter skin is correlated with a higher amount of pheomelanin^[3].

Hyperpigmentation is caused by the exposure to ultraviolet radiation, resulting in the formation of reactive oxygen and nitrogen species between cells^[5]. Increased tyrosinase activity is the critical cellular event. When cells are exposed to ultraviolet radiation, they produce an excessive amount of reactive oxygen and nitrogen species. By inhibiting these free radicals, oral antioxidants can help to reduce melanogenesis^[3].

One of the earliest pieces of evidence of the association between thiols and skin came from the effect of an extract of human skin that contained an active sulfhydryl-containing compound. It prevented melanin formation by tyrosinase inhibition. Hyperpigmentation was observed when this compound got oxidized and inactivated by factors such as heat, radiation and inflammation with consequent loss of the inhibitory effect on tyrosinase. The physical and biochemical evidence prove that this “sulfhydryl compound” was glutathione^[3]. 

Several mechanisms for glutathione’s hypopigmentary action have been hypothesized, with tyrosinase inhibition being the most important. Tyrosinase activity can be reduced by glutathione in three ways. Tyrosinase (the key enzyme in melanogenesis) is directly inactivated by attaching to the copper-containing active site of the enzyme. Second, glutathione interferes with the cellular transfer of tyrosinase to premelanosomes, a prerequisite for melanin synthesis. Finally, the antioxidant activity of tyrosinase inhibits it indirectly. Glutathione shifts melanogenesis from eumelanin to phaeomelanin synthesis by reactions between thiol groups and dopaquinone leading to the formation of sulfhydryl-dopa conjugates^[3].

GLUTATHIONE AND OXIDATIVE STRESS

Oxidative stress, which is caused by an imbalance between reactive oxygen species (ROS) and protective antioxidants, affects men and women throughout their reproductive lives. Although reactive oxygen species are important signaling molecules in physiological activities, excessive quantities of these molecules can potentially cause pathogenic processes in the reproductive tract and reproduction. ROS can modulate cellular functions and oxidative stress (OS) can disturb the intracellular milieu, resulting in diseased cells or endanger cell survival. Antioxidants work to counteract ROS generation by scavenging existing free radicals and promoting the repair of ROS-induced damage to cell structures under normal conditions^[4].

Glutathione is the mother of all antioxidants, the master detoxifier and the immune system’s maestro. It is a significant endogenous antioxidant produced by cells that participates directly in the neutralization of free radicals and reactive oxygen species, as well as maintaining the reduced forms of exogenous antioxidants like vitamins C and E^[4].

In mammalian cells, glutathione, a tripeptide thiol, is the most abundant non-protein sulfhydryl molecule. This thiol plays a prominent role in detoxification and antioxidation of exogeneous and endogenous compounds, as well as maintaining the intracellular redox status. Glutathione is a natural reservoir of reducing power, which can be quickly used by the cells as defense against oxidative stress. The sulfhydryl group (SH) of glutathione confers its protective action against oxidative damage. The protective action of glutathione against reactive oxygen species (ROS) is facilitated by the interactions with its associated enzymes, such as glutathione peroxidase and glutathione reductase^[4].

GLUTATHIONE AND WRINKLE

At least in some anatomic regions, glutathione was found to be significantly superior to placebo in terms of improving wrinkles. This is a fascinating and novel discovery, because cutaneous aging is a big problem that affects the majority of people of all ages. As the world’s populations are rapidly heading toward an aging society and human life spans are increasing, this problem will almost probably become more serious in the near future. When compared to popping a tablet, applying topical antiwrinkle preparation to the entire skin is both expensive and in many cases impractical for the elderly. The findings that both forms of glutathione showed trends in enhanced skin elasticity at various sites, including sun-exposed and sun-protected skin, are also significant^[6].

GLUTATHIONE AND MELASMA

Melasma has a complex etiology. UV light has been shown in clinical and laboratory studies to trigger and exacerbate the condition. UV light is considered to promote melanogenesis and induce reactive oxygen species (ROS) through activating inducible nitric oxide^[7].

Glutathione has also been studied as supplement with positive results. In a 4-week randomized controlled trial in the Philippines, those who took oral glutathione had less melanin than those who took a placebo. Glutathione is thought to act as an anti-oxidant that decreases inflammation^[7].

ADVERSE EFFECTS OF GLUTATHIONE

Other potential adverse effects of high dose and long-term glutathione supplementation include:

• Lightening of hair color: This is a logical result given that hair color is determined by the amount and type of melanin present, which can be influenced by glutathione supplementation. This adverse effect has not yet been clinically reported^[2].
• Depletion of natural hepatic stores of glutathione: Long-term supplementation with any external synthetic chemical might theoretically cause the body to stop producing its own, resulting in a dependency on synthetic supplements. Depletion of glutathione levels in the liver (the site of glutathione storage) may be devastating to health. Although not clinically recorded until recently, this possible side effect is similar to the hypothalamic-pituitary axis suppression seen with long-term use of systemic corticosteroids^[3].
• Increased susceptibility to melanoma: Theoretically, long-term administration of systemic glutathione switches eumelanin to pheomelanin, and may increase the susceptibility towards development of melanoma in the long run^[3].

REFERENCES

1. Forman H, Zhang H, Rinna A. Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med. [Internet]. 2009 [cited 2022 Feb 21]; 30: 1-12. Available from:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2696075/           
2. Minich D, Brown B. A Review of Dietary (Phyto) Nutrients for Glutathione Support. Nutrients. [Internet]. 2019 [cited 2022 Feb 21]; 11: 1-20. Available from:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770193/               
3. Sonthalia S, Daulatabad D, Sarkar R. Glutathione as a skin whitening agent: Facts, myths, evidence and controversies. Indian Journal Dermatology Venereology Leprology. [Internet]. 2016 [cited 2022 Feb 21]; 82: 262-72. Available from:http://ijdvl.com/glutathione-as-a-skin-whitening-agent-facts-myths-evidence-and-controversies/                
4. Adeoye O, Olawumi J, Opeyemi A, Christiania O. Review on the role of glutathione on oxidative stress and infertility. JBRA Assisted Reproduction. [Internet]. 2018 [cited 2022 Feb 21]; 22: 61-6. Available from:http://www.ncbi.nlm.nih.gov/pmc/articles/
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5. Sitohang I, Ninditya S. Systemic Glutathione as a Skin-Whitening Agent in Adult. Dermatology Research Practice. [Internet]. 2020 [cited 2022 Feb 21]. Available from:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196133/            
6. Weschawalit S, Thongthip S, Phutrakool P, Asawanonda P. Glutathione and its antiaging and antimelanogenic effects. Clinical, Cosmetic and Investigational Dermatology. [Internet]. 2017 [cited 2022 Feb 21]; 10: 147-53. Available from:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413479/
7. Ogbechie-Godec O, Elbuluk N. Melasma: an Up-to-Date Comprehensive Review. Dermatol Ther (Heidelb). [Internet]. 2017 [cited 2022 Feb 21]; 7: 305-18. Available from:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574745/